Trisubstituted thioxanthines

ABSTRACT

Disclosed are compounds of the formula: ##STR1## wherein R 1 , R 3  and R 8  are independently alkyl, aryl or aralkyl, and R 2  is selected from the group consisting of S and O, R 6  is selected from the group consisting of S and O, provided that R 2  and R 6  are not both O. The compounds are effective PDE IV inhibitors and possess improved PDE IV inhibition and improved selectivity with regard to PDE III inhibition. Methods of treatment using the compounds are also disclosed.

BACKGROUND OF THE INVENTION

This application is a continuation of application Ser. No. 08/476,262filed Jun. 7, 1995, now abandoned, which is a continuation in part ofU.S. Ser. No. 08/354,664, filed on Dec. 13, 1994, abandoned thedisclosure of which is incorporated herein in its entirety.

Asthma is a complex disease involving the concerted actions of multipleinflammatory and immune cells, spasmogens, inflammatory mediators,cytokines and growth factors. In recent practice there have been fourmajor classes of compounds used in the treatment of asthma, namelybronchodilators (e.g., beta-adrenoceptor agonists), anti-inflammatoryagents (e.g., corticosteroids), prophylactic anti-allergic agents (e.g.,cromolyn sodium) and xanthines (e.g., theophylline) which appear topossess both bronchodilating and anti-inflammatory activity.

Theophylline has been a preferred drug of first choice in the treatmentof asthma. Although it has been touted for its direct bronchodilatoryaction, theophylline's therapeutic value is now believed to also stemfrom anti-inflammatory activity. Its mechanism of action remainsunclear. However, it is believed that several of its cellular activitiesare important in its activity as an anti-asthmatic, including cyclicnucleotide phosphCodiesterase inhibition, adenosine receptor antagonism,stimulation of catecholamine release, and its ability to increase thenumber and activity of suppressor T-lymphocytes. While all of theseactually may contribute to its activity, only PDE inhibition may accountfor both the anti-inflammatory and bronchodilatory components. However,theophylline is known to have a narrow therapeutic index, and a widerange of untoward side effects which are considered problematic.

Of the activities mentioned above, theophylline's activity in inhibitingcyclic nucleotide phosphodiesterase has received considerable attentionrecently. Cyclic nucleotide phosphodiesterases (PDEs) have receivedconsiderable attention as molecular targets for anti-asthmatic agents.Cyclic 3',5'-adenosine monophosphate (cAMP) and cyclic 3',5'-guanosinemonophosphate (cGMP) are known second messengers that mediate thefunctional responses of cells to a multitude of hormones,neurotransmitters and autocoids. At least two therapeutically importanteffects could result from phosphodiesterase inhibition, and theconsequent rise in intracellular (cAMP) or (cGMP) in key cells in thepathophysiology of asthma. These are smooth muscle relaxation (resultingin bronchodilation) and anti-inflammatory activity.

It has become known that there are multiple, distinct PDE isoenzymeswhich differ in their cellular distribution. A variety of inhibitorspossessing a marked degree of selectivity for one isoenzyme or the otherhave been synthesized.

The structure-activity relationships (SAR) of isozyme-selectiveinhibitors has been discussed in detail, e.g., in the article ofTheodore J. Torphy, et al., "Novel Phosphodiesterase Inhibitors For TheTherapy Of Asthma", Drug News & Prospectives, 6(4) May 1993, pages203-214. The PDE enzymes can be grouped into five families according totheir specificity toward hydrolysis of cAMP or cGMP, their sensitivityto regulation by calcium, calmodulin or cGMP, and their selectiveinhibition by various compounds. PDE I is stimulated by Ca²⁺/calmodulin. PDE II is cGMP-stimulated, and is found in the heart andadrenals. PDE III is cGMP-inhibited, and inhibition of this enzymecreates positive inotropic activity. PDE IV is cAMP specific, and itsinhibition causes airway relaxation, anti-inflammatory andantidepressant activity. PDE V appears to be important in regulatingcGMP content in vascular smooth muscle, and therefore PDE V inhibitorsmay have cardiovascular activity.

While there are compounds derived from numerous structure activityrelationship studies which provide PDE III inhibition, the number ofstructural classes of PDE IV inhibitors is relatively limited. Analoguesof rolipram, which following structural formula: ##STR2## and ofRo-20-1724, which has the following structural formula: ##STR3## havebeen studied.

Rolipram, which was initially studied because of its activity as anantidepressant has been shown to selectively inhibit the PDE IV enzymeand this compound has since become a standard agent in theclassification of PDE enzyme subtypes. There appears to be considerabletherapeutic potential for PDE IV inhibitors. Besides initial worksuggesting an antidepressant action, rolipram has been investigated forits anti-inflammatory effects, particularly in asthma. In-vitro,rolipram, Ro-201724 and other PDE IV inhibitors have been shown toinhibit (1) mediator synthesis/release in mast cells, basophils,monocytes and eosinophils; (2) respiratory burst, chemotaxis anddegranulation in neutrophils and eosinophils; and (3) mitogen-dependentgrowth and differentiation in lymphocytes (The PDE IV Family OfCalcium-Phosphodiesterases Enzymes, John A. Lowe, III, et al., Drugs ofthe Future 1992, 17(9):799-807).

Other PDE-IV inhibitors are 3,8-alkyl-disubstituted-6-thioxanthinesdisclosed by U.S. Pat. No. 4,925,847, issued May 15, 1990 to Hofer, thedisclosure of which is incorporated by reference herein in its entirety.

PDE IV is present in all the major inflammatory cells in asthmaincluding eosinophils, neutrophils, T-lymphocytes, macrophages andendothelial cells. Its inhibition causes down-regulation of cellularactivation and relaxes smooth muscle cells in the trachea and bronchus.On the other hand, inhibition of PDE III, which is present inmyocardium, causes an increase in both the force and rate of cardiaccontractility. These are undesirable side effects for ananti-inflammatory agent. Theophylline, a non-selective PDE inhibitor,inhibits both PDE III and PDE IV, resulting in both desirableanti-asthmatic effects and undesirable cardiovascular stimulation. Withthis well-known distinction between PDE isozymes, the opportunity forconcomitant anti-inflammatory and bronchodilator activity without manyof the side effects associated with theophylline therapy is apparent.The increased incidence of morbidity and mortality due to asthma in manyWestern countries over the last decade has focused the clinical emphasison the inflammatory nature of this disease and the benefit of inhaledsteroids.

Additional thioxanthine compounds are known to the art. However,although some have been suggested to be useful for treating, e.g.,asthma, the specific anti-PDE IV activity of these compounds has notbeen determined. For example, French Pharmaceutical Patent No. 835818issued on Aug. 12, 1960 to May & Baker, Ltd, discloses the synthesis ofthe disubstituted thioxanthines 3-butyl-1-methyl-6-thioxanthine and3-isobutyl-1-methyl-6-thioxanthine for bronchial or coronary arterydilation without disclosing any PDE IV inhibitory effects. French PatentNo. 835818 also discloses trisubstituted 6-thioxanthines (Formula I ofthe 188M patent) having at the 1 and 3 positions an alcohol or alkyl(C₁₋₆), straight or branched and H or an alcohol (C₁₋₆) at the 8position.

Woolridge et al., 1962, J. Chem. Soc. Annex IV: 1863-1868 discloses thesynthesis of disubstituted 6-thioxanthines: 1,3 and 3,7-disubstituted6-thioxanthines for bronchial or coronary dilation as well as 1,3,8lower tri-alkyl substituted 6-thioxanthines where the alkyl groups aremethyl or ethyl. PDE IV activity was uncharacterized.

Armitage et al., 1961, Brit. J. Pharm. 17:196-207, disclosetrisubstituted 6-thioxanthines having bronchial and coronary dilatoractivity. The 1,3,8-trisubstituted 6-thioxanthines disclosed by Armitageare 1,3,8-trimethyl-6-thioxanthine and1,3-dimethyl-8-ethyl-6-thioxanthine.

Some trisubstituted xanthine derivatives having diuretic, renalprotective and vasodilator properties are disclosed by U.S. Pat. No.5,068,236, issued to Suzuki et al. on Nov. 26, 1991. Suzuki et al.disclose xanthines, including trisubstituted xanthines having a loweralkyl independently at positions 1 and 3 and a --CH₂ --(R⁴)R⁵ at the 8position, wherein R⁴ and R⁵ are independently substituted orunsubstituted alicyclic alkyl or substituted or unsubstituted aryl. Theexemplified trisubstituted compounds having bronchial and coronarydilator activity are not characterized as to PDE IV activity.

Therefore, there remains a continuing need to find new thioxanthinecompounds having more selective and improved PDE IV inhibitory activity.

OBJECTS AND SUMMARY OF THE INVENTION

It is accordingly a primary object of the present invention to providenew compounds which are more effective selective PDE IV inhibitors.

It is another object of the present invention to provide new compoundswhich act as effective PDE IV inhibitors with lower PDE III inhibition.

It is a further object of the present invention to provide new compoundswhich have a superior PDE IV inhibitory effect as compared totheophylline, disubstituted 6-thioxanthines or other known compounds.

It is another object of the present invention to provide methods fortreating a patient requiring PDE IV inhibition.

It is another object of the present invention to provide new compoundsfor treating disease states associated with abnormally highphysiological levels of cytokines, including tumor necrosis factor.

It is another object of the present invention to provide a method ofsynthesizing the new compounds of this invention.

It is another object of the present invention to provide a method fortreating a patient suffering from disease states such as asthma,allergies, inflammation, depression, dementia, a disease caused by HumanImmunodeficiency Virus and disease states associated with abnormallyhigh physiological levels of cytokines.

Other objects and advantages of the present invention will becomeapparent from the following detailed description thereof.

With the above and other objects in view, the present inventioncomprises compounds of Formula I as follows. ##STR4## wherein: R¹ and R³are aralkyl, R⁸ is alkyl, aryl or aralkyl, R² is S or O, R⁶ is S or O,and R² and R⁶ are not both O;

R⁸ is optionally cycloalkyl, aryl or aralkyl and may be an alkyl,straight or branched, such as methyl, ethyl, isopropyl, n-propyl,cyclopropyl, butyl and pentyl; and

one of R¹ and R³ is benzyl.

R¹, R³ and R⁸ are optionally substituted by halogen, hydroxy, hydroxy,C₁ -C₄ alkoxy, C₁ -C₇ cycloalkoxy, oxo, oximido, carbamido orhydroxycarbimido.

Some particularly preferred compounds in accordance with the presentinvention include:

1,3-Di-(4-chlorobenzyl)-8-isopropyl-6-thioxanthine;

3-(3-Cyclopentyloxy-4-methoxy-benzyl)-1-ethyl-8-isopropyl-6-thioxanthine;

1,3-diethyl-8-cyclopropyl-2,6-dithioxanthine; and

1,3-diethyl-8-(isopropyl)-6-thioxanthine.

The invention also comprises pharmaceutical compositions including aneffective amount of a compound according to Formula (I), or a saltthereof, together with a pharmaceutically acceptable carrier. Thepharmaceutically acceptable carrier is suitable for administration ofthe pharmaceutical composition orally, topically, by suppository,inhalation, insufflation, and parenterally and any other suitable methodfor administering a medication.

The invention also provides methods for selectively inhibiting PDE IVenzyme activity in a patient requiring the same by administering acompound according to the invention by administering an effective amountof a pharmaceutically acceptable compound according to the invention.

Alternatively, the invention provides methods for treating a patientsuffering from a disease or disorder such as asthma, allergies,inflammation, depression, dementia, atopic diseases, rhinitis anddisease states associated with abnormally high physiological levels ofcytokine by administering an effective amount of a pharmaceuticallyacceptable compound according to the invention.

Both methods comprise administering an effective amount of the compoundin a pharmaceutically acceptable form according to Formula (I) wherein:

R¹, R³ and R⁸ are independently alkyl, aryl or aralkyl;

R² is selected from the group consisting of S and O;

R⁶ is selected from the group consisting of S and O, provided that R²and R⁶ are not both O.

Within this formula, the aryl group may be substituted or unsubstituted.The alkyl may be straight or branched and can be cycloalkyl. Inparticular, the alkyl can be methyl, ethyl, isopropyl, n-propyl,cyclopropyl, butyl or pentyl.

R¹, R³ and/or R⁸ are optionally substituted by halogen, hydroxy, C₁ -C₄alkoxy, C₁ -C₇ cycloalkoxy, oxo, oximido, carbamido or hydroxycarbimido.

Optionally, one of R¹ and R³ is benzyl.

In preferred aspects of the invention, the method includes administeringone of the following compounds:

1,3,8-triethyl-2,6dithioxanthine;

1,3,8-triethyl-2-dithioxanthine;

8-cyclopropyl-1-ethyl-3-(2-methyl butyl)-6-thioxanthine;

1,8-diethyl-3-(2-methylbutyl)-6-thioxanthine;

3-ethyl-1-methyl-8-isopropyl-6-thioxanthine;

1,3-diethyl-8-(isopropyl)-6-thioxanthine;

8-cyclopropyl-1,3-dipropyl-6-thioxanthine;

8-ethyl-1,3-dipropyl-6-thioxanthine;

8-isopropyl-1,3-dipropyl-6-thioxanthine;

1,3-diethyl-8-cyclopropyl-2,6-dithioxanthine;

1,3-Di-(4-chlorobenzyl)-8-isopropyl-6-thioxanthine;

3-(3-Cyclopentyloxy-4-methoxy-benzyl)-1-ethyl-8-isopropyl-6-thioxanthine;

1-(4-chlorobenzyl)-3-ethyl-8-isopropyl-6-thioxanthine; and

3-(4-chlorobenzyl)-1-ethyl-8-isopropyl-6-thioxanthine.

An alternative aspect of the invention includes a method of treatmentwhich involves administering an effective amount of a pharmaceuticallyacceptable compound according to the invention having anti-inflammatoryand/or immunosuppressant activity, to a patient in need of suchtreatment.

When R¹ and R³ of the compound are independently aryl, or arylalkyl andhave bronchodilator activity, the method of treatment according to theinvention involves administering the compound to a patient in need ofsuch treatment.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides reaction scheme 1 exemplifying preparation of certaincompounds according to the invention.

FIG. 2 provides reaction scheme 2 exemplifying preparation of certaincompounds according to the invention.

DETAILED DISCLOSURE OF THE INVENTION

The compounds of the present invention, as demonstrated in the appendedexamples, are effective in the mediation or inhibition of PDE IV enzymeactivity in need of such treatment. Further, these compounds areselective PDE IV inhibitors which possess bronchodilatory,anti-inflammatory and other properties characteristic of PDE IVinhibitors substantially without undesirable cardiovascular stimulationcaused by PDE III inhibition. Many of these compounds have asubstantially equal or superior PDE IV inhibitory effect as compared totheophylline, disubstituted 6-thioxanthines and other previously knownPDE IV inhibitors.

Accordingly the present invention provides novel compounds havingunexpectedly superior PDE IV inhibitory activity and novel methods fortreating diseases or disorders related to PDE IV enzyme activity. Thecompounds according to the invention mainly comprise compounds ofFormula I as follows. ##STR5## wherein: R¹ and R³ are aralkyl,substituted or unsubstituted and R⁸ is alkyl, aryl or aralkyl. Thearalkyl can be benzyl. In one embodiment, R² and R⁶ are independently Sor O, but are not both O.

The alkyl moieties can be straight, branched or cyclic. R¹, R³ and R⁸may have substituents such as halogen, hydroxy, C₁ -C₄ alkoxy, C₁ -C₇cycloalkoxy, oxo, oximido, carbamido or hydroxycarbimido. Preferablealkyl moieties include lower alkyls such as methyl, ethyl, isopropyl,n-propyl, cyclopropyl, butyl and pentyl, straight or branched. The alkylportion of the aralkyl moieties is preferably a lower alkyl. The term"lower alkyl" is defined for purposes of the present invention asstraight or branched chain radicals having from 1 to 8 carbon atoms. Inone embodiment, R⁸ is propyl and preferably isopropyl.

In a preferred embodiment, the compound is one of the following:

1,3-Di-(4-chlorobenzyl)-8-isopropyl-6-thioxanthine;

3-(3-Cyclopentyloxy-4-methoxy-benzyl)-1-ethyl-8-isopropyl-6-thioxanthine;

1,3-diethyl-8-cyclopropyl-2,6-dithioxanthine; and

1,3-diethyl-8-(isopropyl)-6-thioxanthine.

The invention also provides for methods of selectively inhibiting theenzyme PDE IV in a patient, in order to treat a disease or disorderrelated to elevated PDE IV activity in a patient as enumerated above.The method of treatment comprises administering to a patient in needthereof an effective dose of a pharmacologically active compound havingPDE IV inhibitory activity and a structure according to Formula I,supra, wherein:

R¹, R³ and R⁸ are alkyl, aryl or aralkyl, substituted or unsubstituted.In one embodiment, R² and R⁶ are independently S or O, but are not bothO.

The alkyl moieties can be straight, branched or cyclic. R¹, R³ and R⁸may have substituents such as halogen, hydroxy, C₁ -C₄ alkoxy, C₁ -C₇cycloalkoxy, oxo, oximido, carbamido or hydroxycarbimido. Preferablealkyl moieties include lower alkyls such as methyl, ethyl, isopropyl,n-propyl, cyclopropyl, butyl and pentyl, straight or branched. The alkylportion of the aralkyl moieties is preferably a lower alkyl. The term"lower alkyl" is defined for purposes of the present invention asstraight or branched chain radicals having from 1 to 8 carbon atoms.

In one embodiment, R¹ is an alkyl of C₁₋₃, straight or branched, R³ isan alkyl of C₁₋₅, straight or branched and R⁸ is ethyl or propyl,including cyclopropyl and isopropyl.

In another embodiment, R¹ and R³ are aralkyl, substituted orunsubstituted and R² and R⁶ are S or O, but R² and R⁶ are not both O andR⁸ is alkyl or cycloalkyl, aryl or aralkyl, substituted orunsubstituted. Preferably, R⁸ is propyl and more preferably, isopropyl.

Optionally, R¹ and R³ are not C₁₋₆ alkyl or alcohol when R⁸ is a C₁₋₆alcohol. In another option, R¹, R³ and R⁸ are not methyl or ethyl. In afurther option, R¹ and R³ are not lower alkyl when R⁸ is --CH₂ --(R^(a))R^(b), wherein R^(a) and R^(b) are independently substituted orunsubstituted alicyclic alkyl or substituted or unsubstituted aryl. In aparticular option, R¹, R³ and R⁸ are not all methyl and when R¹ and R³are both methyl, R⁸ is not ethyl.

The present invention is further related to a method for the treatmentof allergic and inflammatory disease which comprises administering to apatient in need thereof an effective amount of the compounds of thepresent invention able to selectively inhibit PDE IV.

The compounds of the present invention may find use in the treatment ofother diseases or disorders, such as, for example, in the treatment ofdisease states associated with a physiologically detrimental excess oftumor necrosis factor (TNF). TNF activates monocytes, macrophages andT-lymphocytes. This activation has been implicated in the progression ofHuman Immunodeficiency Virus (HIV) infection and other disease statesrelated to the production of TNF and other cytokines modulated by TNF.

In a particular embodiment, the method of treatment involvesadministering compounds of the present invention havinganti-inflammatory and/or immunosuppressants to a patient in need of suchtreatment.

In another particular embodiment, the method of treatment involvesadministering a compound of the present invention, wherein R¹ and R² areindependently aryl or arylalkyl, to a patient in need of such treatment.

Within the formula set forth above, the following compounds areparticularly preferred:

1,3,8-triethyl-2,6-dithioxanthine;

1,3,8-triethyl-2-dithioxanthine;

8-cyclopropyl-1-ethyl-3-(2 methyl butyl)-6-thioxanthine;

1,8-diethyl-3-(2-methylbutyl)-6-thioxanthine;

3-ethyl-1-methyl-8-isopropyl-thioxanthine;

1,3-diethyl-8-isopropyl-6-thioxanthine;

8-ethyl-1,3-dimethyl-6-thioxanthine;

8-cyclopropyl-1,3-dipropyl-6-thioxanthine;

8-ethyl-1,3-dipropyl-6-thioxanthine;

8-isopropyl-1,3-dipropyl-6-thioxanthine;

1,3-diethyl-8-cyclopropyl-2,6-dithioxanthine

1,3-Di-(4-chlorobenzyl)-8-isopropyl-6-thioxanthine

3-(3-Cyclopentyloxy-4-methoxy-benzyl)-1-ethyl-8-isopropyl-6-thioxanthine

1-(4-chlorobenzyl)-3-ethyl-8-isopropyl-6-thioxanthine; and

3-(4-chlorobenzyl)-1-ethyl-8-isopropyl-6-thioxanthine.

The compounds of the present invention have been found to be highlyeffective PDE IV inhibitors, the inhibition of which is in factsignificantly and surprisingly greater than that of, for example,theophylline, disubstituted 6-thioxanthines and aryl thioxanthines.

In Example 14 there is provided a comparison of analogous disubstitutedand trisubstituted xanthines which illustrate the advantages oftrisubstituted xanthines. The trisubstituted compounds according to theinvention have substantially lower PDE IV IC50 values, indicating thatthese compounds will have increased potency and/or selectivity in thetreatment of PDE IV related diseases or disorder.

A description of the synthesis of exemplary representatives of thesemolecules is set forth in the Examples. The synthesis of other moleculesnot specifically shown in the examples but within the scope of theinvention are carried out using those techniques shown withmodifications which are known to those of ordinary skill in the art. Anoverview of representative synthetic plans is provided by FIGS. 1 and 2.

Turning now to the Figures, thioxanthines (9) can be prepared, forexample, by two different routes, either starting with aN,N'-disubstituted(thio)urea, which can be applied for R¹ ≦R³, orstarting with a monosubstituted urea followed by alkylation of compoundsof 3,8-disubstituted thioxanthines with R³ ═H, which can be applied inall cases, including R¹ >R³. In Scheme 1, compound (1) (FIG. 1), whereX═O, S, is reacted with compound (2), where R═H or alkyl, to producecompound (3). Steps (4) through (7) provide closure of the secondaromatic ring to produce a xanthine where R⁶ is O. Reactions producingcompounds (7) through (9) provide a 6-thioxanthine as compound (9).

In FIG. 2, Scheme 2, compound (6) from Scheme 1, wherein X═O and R¹ ═H,is further reacted to substitute an alkyl or aryl at R¹. Thisillustrates the manner in which R¹ or other substituents may be readilysubstituted as required in e.g., compounds (9). An alkyl in Schemes 1and 2 is C₁₋₈, straight, branched, cyclic, substituted or unsubstitutedwith groups such as halogen, hydroxy, oxo, oximido, carbamido orhydroxycarbimido.

The compounds of the present invention can be administered to anyonerequiring PDE IV inhibition. Administration may be orally, topically, bysuppository, inhalation or insufflation, or parenterally.

The present invention also encompasses, where appropriate, allpharmaceutically acceptable salts of the foregoing compounds. Oneskilled in the art will recognize that acid addition salts of thepresently claimed compounds may be prepared by reaction of the compoundswith the appropriate acid via a variety of known methods. Alternatively,alkali and alkaline earth metal salts are prepared by reaction of thecompounds of the invention with the appropriate base via a variety ofknown methods.

Various oral dosage forms can be used, including such solid forms astablets, gelcaps, capsules, caplets, granules, lozenges and bulk powdersand liquid forms such as emulsions, solution and suspensions. Thecompounds of the present invention can be administered alone or can becombined with various pharmaceutically acceptable carriers andexcipients known to those skilled in the art, including but not limitedto diluents, suspending agents, solubilizers, binders, disintegrants,preservatives, coloring agents, lubricants and the like.

When the compounds of the present invention are incorporated into oraltablets, such tablets can be compressed, tablet triturates,enteric-coated, sugar-coated, film-coated, multiply compressed ormultiply layered. Liquid oral dosage forms include aqueous andnonaqueous solutions, emulsions, suspensions, and solutions and/orsuspensions reconstituted from non-effervescent granules, containingsuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, coloring agents, and flavorings agents. When thecompounds of the present invention are to be injected parenterally, theymay be, e.g., in the form of an isotonic sterile solution.Alternatively, when the compounds of the present invention are to beinhaled, they may be formulated into a dry aerosol or may be formulatedinto an aqueous or partially aqueous solution.

In addition, when the compounds of the present invention areincorporated into oral dosage forms, it is contemplated that such dosageforms may provide an immediate release of the compound in thegastrointestinal tract, or alternatively may provide a controlled and/orsustained release through the gastrointestinal tract. A wide variety ofcontrolled and/or sustained release formulations are well known to thoseskilled in the art, and are contemplated for use in connection with theformulations of the present invention. The controlled and/or sustainedrelease may be provided by, e.g., a coating on the oral dosage form orby incorporating the compound(s) of the invention into a controlledand/or sustained release matrix.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms, are described in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986), incorporated by reference herein. Techniques andcompositions for making solid oral dosage forms are described inPharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz,editors) 2nd edition, published by Marcel Dekker, Inc., incorporated byreference herein. Techniques and compositions for making tablets(compressed and molded), capsules (hard and soft gelatin) and pills arealso described in Remington's Pharmaceutical Sciences (Arthur Osol,editor), 1553-1593 (1980), incorporated herein by reference. Techniquesand composition for making liquid oral dosage forms are described inPharmaceutical Dosage Forms: Disperse Systems, (Lieberman, Rieger andBanker, editors) published by Marcel Dekker, Inc., incorporated hereinby reference.

When the compounds of the present invention are incorporated forparenteral administration by injection (e.g., continuous infusion orbolus injection), the formulation for parenteral administration may bein the form of suspensions, solutions, emulsions in oily or aqueousvehicles, and such formulations may further comprise pharmaceuticallynecessary additives such as stabilizing agents, suspending agents,dispersing agents, and the like. The compounds of the invention may alsobe in the form of a powder for reconstitution as an injectableformulation.

The dose of the compounds of the present invention is dependent upon theaffliction to be treated, the severity of the symptoms, the route ofadministration, the frequency of the dosage interval, the presence ofany deleterious side-effects, and the particular compound utilized,among other things.

In addition, the PDE IV inhibitory compounds of the present inventionmay be examined for their PDE IV inhibitory effects via the techniquesset forth in the following examples, wherein the ability of thecompounds to inhibit PDE IV isolated from bovine tracheal smooth muscleis set forth.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention, and are not to be construed to limit the claims in any mannerwhatsoever.

EXAMPLE 1 1,3-Diethyl-8-cyclopropyl-2,6-dithioxanthine

A. 1,3-Diethyl-8cyclopropyl-2-thioxanthine

25.1 g (100 mM) of 5,6-diamino-1,3-diethyl-2-thiouracil HCl weredissolved in 400 ml of pyridine, 12.72 g (120 mM) of sodium carbonateadded, and under cooling a solution of 10.77 ml (120 mM) ofcyclopropanecarbonyl chloride in 50 ml of dried ether added within 10min. After 20 min the solvents were evaporated in vacuo. The residue wastreated with 200 ml of water and about 50 ml were removed again invacuo. The suspension was diluted with 100 ml of 2N aqueous sodiumhydroxide (NaOH) and heated under reflux for 30 min. A further 80 mlwere distilled off during this time. After cooling the solution wasacidified with 5N aqueous hydrochloric acid (HCl) to pH 5.5; 200 ml ofwater was added and the resulting suspension filtered. The solid wascollected and washed, redissolved in 200 ml of 1N NaOH, treated twicewith 0.4 g of charcoal, filtered and acidified again to pH 4.5. Thesolid was collected again, washed and dried to give 25.5 g of a solidwhich was suspended in 400 ml of hot methanol. The solid was collectedagain, washed and dried to give 23.5 g (89.0%) of 2-thioxanthine with mpsubl 265-7° C.

B. 1,3-diethyl-8-cyclopropyl-2,6-dithioxanthine

13.22 g (50 mM) of 2-thioxanthine and 13.34 g (60 mM) of phosphoruspentasulfide were heated under reflux in 160 ml of pyridine for 3 days.At 5-10° C., 66 ml (132 mM) of 2N NaOH were added. The solvents wereevaporated in vacuo, the residue treated with 200 ml of water andevaporated again. The residue was again suspended in 200 ml of water andcollected. The crude product was dissolved in 120 ml of 1N NaOH, treatedtwice with 0.14 g of charcoal, filtered and acidified with 32 ml of 5NHCl to pH 4.5. The solid was collected, washed and dried to give 14.31 gof crude dithioxanthine. This was dissolved in 300 ml of chloroform;some insoluble material was filtered off, and the solution passedthrough 71.5 g of silica gel in a column. Crystallization fromisopropanol gave 12.17 g (86.8%) of 2,6-dithioxanthine with mp 196-200°C.

Elemental analysis for C₁₂ H₁₆ N₄ S₂ : Calculated: C 51.40 H 5.75 N19.98 S 22.87 Found: C 51.87 H 5.88 N 20.33 S 22.61

EXAMPLE 2 3-(4-Chlorobenzyl)-1ethyl-8-isopropyl-6-thioxanthine

A. 3-(4-Chlorobenzyl)-1-ethyl-8-isopropyl-xanthine

13.47 g (40 mM) of 6amino-1-(4-chlorobenzyl)-5-isobutyrylaminouracilwere dissolved in 130 ml of DMF, treated at 5° C. with 4.57 g (40.8 mM)potassium t-butoxide and after dissolution, 3.28 ml (44 mM) ofethylbromide added. After 3 hr another 1.14 g of t-BuOK and 1.64 ml ofethylbromide were added. After a further 1.5 hr, 1.64 ml of ethylbromidewere supplemented. After a total of 22 hr the solution was neutralizedwith 1N HCl to pH 7 and the solvents evaporated in vacuo. The residuewas taken up in dichloromethane-water and the organic phase collectedgiving 17.66 of crude 3-ethyl uracil, which was dissolved in 17.6 ml of1N NaOH and heated under reflux for 1 hr. The solution was treated twicewith 1 g of charcoal, filtered and neutralized with 5N HCl to pH 7. Thesolid was diluted with water, collected, and dried. The crude materialwas recrystallized from methanol to give 7.42 g (49.2%) of3-(4-chlorobenzyl)-1-ethyl-8-isopropyl-xanthine, mp 221-2° C.

B. 3-(4-Chlorobenzyl)-1-ethyl-8-isopropyl-6-thioxanthine

6.59 g (19 mM) of xanthine and 5.07 g (22.8 mM) of phosphoruspentasulfide were heated under reflux in 102 ml of pyridine for 3 days.At 0° C., 25.1 ml of 2N NaOH were added. The solid was filtered off andwashed with pyridine. The solvents were evaporated in vacuo, the residuesuspended in water, collected, redissolved in 100 ml of 1N NaOH and 50ml of iso-propanol, treated twice with 0.3 g of charcoal, filtered andneutralized with 5N HCl to pH 7. The isopropanol was removed in vacuoand the solid collected, washed and dried to give 6.80 g (98.7%) of6-thioxanthine, mp 188-9° C.

Elemental analysis for C₇ H₁₉ ClN₄ OS: Calculated: C 56.27 H 5.28 N15.44 O 4.41 Found: C 56.25 H 5.33 N 15.47 O 4.41

EXAMPLE 3 1-(4-Chlorobenzyl)-3ethyl-8-isopropyl-6-thioxanthine

A. 1-(4-Chlorobenzyl)-3-ethyl-8-isopropyl-xanthine

3.17 g (28.2 mM) of potassium t-butoxide (t-BuOK) were added to asolution of 6.11 g (27.5 mM) of6-amino-1-ethyl-5-isobutyrylamino-uracil. At 0° C., 4.90 g (30.4 mM) of4-chlorobenzylchloride were added. After 3 hr at 0-5° C., further 1.22 gt-BuOK and 2.45 g of 4-chloro-benzylchloride were added. After further 3hr another 2.45 g of benzylchloride are supplemented. After 3 days (1day is sufficient) the solution was neutralized with 1N HCl and thesolvents evaporated. The residue was suspended in water, the solidcollected and washed. The crude intermediate amide was heated underreflux in 100 ml of 1N NaOH and 10 ml of 1-propanol. After 1 hr themixture was neutralized to pH 7 and extracted with chloroform.Crystallization from dichloromethane (mainly evaporated)--methanol gave2.99 g (31.3%) of the title xanthine, mp 194-5° C. The mother liquorsgave 6.33 g of impure material which was separated on 15 g of silica gelelutions with dichloromethane and gave additional 0.78 g (8.2%) of thexanthine.

B. 1-(4-Chlorobenzyl)-3-ethyl-8-isopropyl-6-thioxanthine

2.77 g (8.0 mM) of xanthine and 2.13 g (9.6 mM) of phosphoruspentasulfide were heated under reflux in 50 ml of pyridine for 7 days.At 0° C., 10.6 ml of 2N NaOH were added within 15 min. The solvents wereevaporated in vacuo and the residue suspended (slow crystallization) inwater. The solid was collected and washed, redissolved in 50 ml of 1NNaOH and 50 ml of isopropanol, treated twice with 0.3 g of charcoal,filtered neutralized with 5N HCl to pH 7. The isopropanol was distilledoff with addition of water and the solid collected, washed and dried togive 2.60 g (89.7%) of crude thioxanthine, which was dissolved in 40 mlof dichloromethane and filtered through 30 g of silica gel: 1.91 g(65.9%) of 6-thioxanthine were recovered, mp 153-4° C.

EXAMPLE 4 1,3-8-Triethyl-2,6dithioxanthine

Using a process analogous to that used for Example 1,1,3,8-triethyl-2,6-dithioxanthine was prepared. A recrystallized samplefrom ether had mp 144-6° C.

Elemental analysis for C₁₁ H₁₆ N₄ S₂ calc. C 49.22 H 6.01 N 20.87 S23.89 found C 49.55 H 6.11 N 20.92 S 23.83

EXAMPLE 5 1,3-Diethyl-8-isopropyl-6-thioxanthine

1,3-diethyl-8-isopropyl-xanthine (6.25 g, 25 mM) (J Amer Chem Soc 1953,75, 114-5) and 6.8 g (30 mM) of phosphorus pentasulfide were refluxed in86 ml of pyridine for 3 days. At 10-20° C., 33.5 ml of 2N NaOH are addedwith cooling. The solid was filtered off and washed with pyridine. Thefiltrate was evaporated in vacuo to dryness, the residue suspended in 50ml of water, adjusted to pH 7.5, the solid collected, washed with waterand dried. The product was redissolved in 30 ml NaOH, treated twice with0.5 g of charcoal, filtered, and acidified with 5N HCl to pH 3. At 5°C., the solid was collected, washed and dried.

Elemental analysis for C₁₂ H₁₈ N₄ OS, calc. C 54.12 H 6.81 N 21.04 S12.04 found C 54.60 H 6.94 N 21.27 S 12.12

EXAMPLE 6 1,3-Dipropyl-8-isopropyl-6-thioxanthine

Using a process analogous to that used for Example 5,1,3-dipropyl-8-isopropyl-6-thioxanthine were prepared, with a yield of97.2%. A recrystallized sample from methanol had mp 133-4° C.

EXAMPLE 7 8-Cyclopropyl-1,3-dipropyl-6-thioxanthine

Using a process analogous to that of Example 5,8-cyclopropyl-1,3-dipropyl-6-thioxanthine was prepared with a mp of170-2° C. The yield was 94.3%.

Elemental analysis for C₁₄ H₂₀ N₄ OS, calc. C 57.51 H 6.89 N 19.16 S10.97 found C 57.38 H 6.99 N 19.26 S 10.92

EXAMPLE 8 8-Cyclopropyl-1-ethyl-3-(2-methyl-butyl)-6-thioxanthine

Using a process analogous to that of Example 5,8-cyclopropyl-1-ethyl-3-(2-methyl-butyl)-6-thioxanthine) was preparedwith an mp of 147-8° C. Yield was 85.4%.

Elemental analysis for C₁₅ H₂₂ N₄ OS, calc. C 58.79 H 7.24 N 18.28 S10.46 found C 58.89 H 7.34 N 18.29 S 10.76

EXAMPLE 9 1,8-Diethyl-3-(2-methyl-butyl)-6-thoxanthine

Using a process analogous to that of Example 5,1,8-diethyl-3-(2-methyl-butyl)-6-thioxanthine) was prepared with a mp of115-7° C. with a mp 170-2° C. Yield was 97.8%.

Elemental analysis for C₁₄ H₂₂ N₄ OS, calc. C 57.11 H 7.53 N 19.03 S10.89 found C 57.18 H 7.67 N 19.19 S 10.76

EXAMPLE 10 1,3-Di-(4-chlorobenzyl)-8-isopropyl-6-thioxanthine

A. 1,3-Di-(4-chlorobenzyl)-8-isopropyl-6-xanthine

Using a process analogous to Example 3, part a,1,3-di-(4-chlorobenzyl)-8-isopropyl-6-xanthine was prepared. The yieldof crude product was 96.5%. Crystallization from chloroform with alittle methanol gave 59.8% yield of xanthine with mp 218-9° C.

B. 1,3-Di-(4chlorobenzyl)-8-isopropyl-6-thioxanthine

Using a process analogous to Example 3, part b,1,3-di-(4-chlorobenzyl)-8-isopropyl-6-thioxanthine was prepared. Theyield of crude product was 87.1%. After filtration through silicagel andrecrystallization from dichloromethane with a little methanol the yieldobtained was 71.1% of thioxanthine with a mp 106-7°/178° C.

Elemental analysis for C₁₄ H₂₂ N₄ OS, calc. C 55.35 H 4.64 N 11.74 S6.70 (H₂ O) found C 55.54 H 4.63 N 11.83 S 6.49

EXAMPLE 11 3-(3-Cyclopentyloxy-4-methoxy-benzyl)-1-ethyl8-isopropyl-6-thioxanthine

A. 3-(3-Cyclopentyloxy-4-methoxy-benzyl)-1-ethyl-8-isopropyl-xanthine

Using a process analogous to that of Example 2, part a,3-(3-cyclopentyloxy-4-methoxy-benzyl)-1-ethyl-8-isopropyl-xanthine wasprepared with a yield of 63.3% and with mp 208-9° C.

B.3-(3-Cyclopentyloxy-4-methoxy-benzyl)-1-ethyl-8-isopropyl-6-thioxanthine

Using a process analogous to Example 2, part b, with the modificationthat the refluxing step was conducted for 13 days,3-(3-cyclopentyloxy-4-methoxy-benzyl)-1-ethyl-8-isopropyl-6-thioxanthinewas prepared.

EXAMPLE 12

Protocols for PDE IV inhibition activity are set forth below:

Type IV Phosphodiesterase Enzyme Isolation Protocol

The Type IV PDE is isolated from bovine tracheal smooth muscle using aprocedure similar to that previously described by Silver, P. J. et al.,Eur. J. Pharmacol. 150:85,1988.(1). Briefly, smooth muscle from bovinetrachea is minced and homogenized using a polytron in 10 volumes of anextraction buffer containing 10 mM Tris-acetate (pH 7.5), 2 mM magnesiumchloride, 1 mM dithiothreitol and 2,000 units/ml of aprotinin. This andall subsequent procedures are performed at 0-4° C. The homogenate issonicated and then centrifuged at 48,000×g for 30 minutes. The resultingsupernatant is applied to a DEAE Trisacryl M column previouslyequilibrated with sodium acetate and dithiothreitol. After applicationsof the sample, the column is washed with sodium acetate/ dithiothreitol,after which the different forms of PDE are eluted from the column usinga linear Tris-HCl/NaCl gradient. Fractions containing Type IV PDE arecollected, dialyzed and concentrated to 14% of the original volume. Theconcentrated fractions are diluted to 50% with ethylene glycol andstored at -20° C.

Measuring Type IV PDE Activity

Enzyme activity is assessed by measuring the hydrolysis of [³ H]-cyclicAMP, as described by Thompson, W. J. et al., Adv. Cyclic Nucleotide Res.10:69, 1979. The cyclic AMP concentration used in this assay is 0.2 mM,which approximates the K_(m) value. Protein concentration is adjusted toensure that no more than 15% of the available substrate is hydrolyzedduring the incubation period.

All test compounds are dissolved in dimethyl sulfoxide (finalconcentration of 2.5%). This concentration of dimethyl sulfoxideinhibits enzyme activity by approximately 10%.

EXAMPLE 13 Comparison of PDE IV IC₅₀ Activity for TrisubstitutedThioxanthines and Disubstituted Thioxanthines

The procedures of Example 12 were used to measure PDE IV activity forexemplary compounds and for some analogous disubstituted thioxanthinecompounds in order to demonstrate the improved PDE IV IC₅₀ activity forthe compounds according to the invention. The results, wherein a lowerPDE IV IC₅₀ number indicates a superior activity, are provided below.

    ______________________________________                                        PDE IV ACTIVITY                                                                                         PDE                                                 Compound                  IV IC.sub.50 (μM)                                ______________________________________                                        8-cyclopropyl-1-ethyl-3-(2 methyl-butyl) 6-thioxanthine-                                                1.18                                                8-cyclopropyl-3-(2-methyl-butyl)-6-thioxanthine                                                         3.83*                                               3-ethyl-8-isopropyl-6-thioxanthine                                                                      4.6*                                                3-ethyl-1-methyl-8-isopropyl-thioxanthine                                                               1.0                                                 1,3-diethyl-8-isopropyl- 6-thioxanthine                                                                 1.2                                                 8-cyclopropyl-3-propyl-6-thioxanthine                                                                   4.47*                                               8-cyclopropyl-1,3-dipropyl-6-thioxanthine                                                               2.97                                                3-propyl-8-ethyl-6-thioxanthine                                                                         18.37*                                              8-isopropyl-3-propyl-6-thioxanthine                                                                     3.3*                                                8-isopropyl-1,3-dipropyl-6-thioxanthine                                                                 1.67                                                ______________________________________                                         *Disubstituted analog.                                                   

As indicated by the results shown by above, the trisubstituted alkylthioxanthines demonstrate an improvement in PDE IV IC₅₀ activity overdisubstituted analogs.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and accompanyingfigures. Such modifications are intended to fall within the scope of theclaims. Various publications are cited herein, the disclosures of whichare incorporated by reference in their entireties.

What is claimed is:
 1. A compound of the formula: ##STR6## wherein R¹ isselected from C₂ -C₆ straight or branched alkyl, C₃ -C₆ cycloalkyl, andaralkyl wherein the alkyl moiety of said aralkyl is straight or branchedor is cycloalkyl, and wherein said alkyl, cycloalkyl and aralkyl areoptionally substituted with halogen, hydroxy, C₁ -C₄ alkoxy, C₃ -C₇cycloalkoxy, oxo, oximido, carbamido or hydroxy carbamido;R² is selectedfrom O and S; R³ is aralkyl wherein the alkyl moiety of said aralkyl isstraight or branched or is cycloalkyl, wherein said aralkyl isoptionally substituted with halogen, hydroxy, C₁ -C₄ alkoxy, C₃ -C₇cycloalkoxy, oxo, oximido, carbamido or hydroxy carbamido; R⁶ isselected from O and S; and R⁸ is selected from isopropyl, n-propyl,cyclopropyl, butyl and pentyl, said butyl and pentyl being straightbranched or cyclic, or aralkyl consisting of an aryl moiety and astraight or branched C₁ -C₈ alkylene moiety, wherein said isopropyl,n-propyl, cyclopropyl, butyl and pentyl, straight, branched or cyclic oraralkyl are optionally substituted with halogen, hydroxy, C₁ -C₄ alkoxy,C₃ -C₇ cycloalkoxy, oxo, oximido, carbamido or hydroxy carbamido,;provided that R² and R⁶ are not both O.
 2. A compound according to claim1, wherein R⁸ is isopropyl or cyclopropyl.
 3. A compound selected fromthe group consisting of 1,3-diethyl-8-cyclopropyl-2,6-dithioxanthine and1,3-diethyl-8-(isopropyl)-6-thioxanthine.
 4. A compound according toclaim 1, wherein R¹, R³ and R⁸ are further substituted by substituentsselected from the group consisting of halogen, hydroxy, C₁ -C₄ alkoxy,C₃ -C₇ cycloalkoxy, or oxo.
 5. A compound according to claim 1, where inR⁸ is a straight chain alkyl or a branched chain alkyl.
 6. A compoundaccording to claim 1, wherein R¹ and R³ are benzyl, optionallysubstituted with halogen, hydroxy, C₁ -C₄ alkoxy, or C₃ -C₇ cycloalkoxy.7. A compound according to claim 1, selected from the group consistingof:3-(4-chlorobenzyl)-1-ethyl-8-isopropyl-6-thioxanthine;1,3-Di-(4chlorobenzyl)-8-isopropyl-6-thioxanthine; and3-(3-Cyclopentyloxy-4-methoxy-benzyl)-1-ethyl-8-isopropyl-6-thioxanthine.8. A pharmaceutical composition comprising a compound according to claim1, or a salt thereof, together with a pharmaceutically acceptablecarrier.
 9. The pharmaceutical composition of claim 8, wherein thecompound is selected from the group consistingof:3-(4-chlorobenzyl)-1-ethyl-8-isopropyl-6-thioxanthine;1,3-Di-(4chlorobenzyl)-8-isopropyl-6-thioxanthine; and3-(3-Cyclopentyloxy-4-methoxy-benzyl)-1-ethyl-8-isopropyl-6-thioxanthine.10. The pharmaceutical composition of claim 8 wherein saidpharmaceutically acceptable carrier is suitable for oral administrationtopical administration, administration by suppository, administration byinhalation, administration by insufflation, or parenteraladministration.
 11. A method of effecting PDE IV inhibition whichcomprises administering to a patient suffering from a disease ordisorder selected from the group consisting of asthma, allergies,inflammation, depression, and rhinitis, a therapeutically effectiveamount of a compound of the formula: ##STR7## wherein: R¹ is selectedfrom C₂ -C₆ straight or branched alkyl, C₃ -C₆ cycloalkyl, and aralkylwherein the alkyl moiety of said aralkyl is straight or branched or iscycloalkyl, wherein said alkyl, cycloalkyl, and aralkyl are optionallysubstituted with halogen, hydroxy, C₁ -C₄ alkoxy, C₃ -C₇ cycloalkoxy,oxo, oximido, carbamido or hydroxy carbamido;R² is selected from O andS; R³ is aralkyl wherein the alkyl moiety of said aralkyl is straight orbranched or is cycloalkyl, wherein said aralkyl is optionallysubstituted with halogen, hydroxy, C₁ -C₄ alkoxy, C₃ -C₇ cycloalkoxy,oxo, oximido, carbamido or hydroxy carbamido; R⁶ is selected from O andS; and R⁸ is selected from isopropyl, n-propyl, cyclopropyl, butyl andpentyl, said butyl and pentyl being straight, branched or cyclic, oraralkyl consisting of an aryl moiety and a straight or branched C₁ -C₈alkylene moiety, wherein said isopropyl, n-propyl, cyclopropyl, butyland pentyl, straight, branched or cyclic, or aralkyl are optionallysubstituted wit halogen, hydroxy, C₁ -C₄ alkoxy, C₃ -C₇ cycloalkoxy,oxo, oximido, carbamido or hydroxy carbamido; provided that R² and R⁶are not both O.
 12. The compound of claim 1 wherein R¹ is aralkylwherein the alkyl moiety of said aralkyl is straight or branched or iscycloalkyl, and wherein said aralkyl is optionally substituted withhalogen, hydroxy, C₁ -C₄ alkoxy, C₃ -C₇ cycloalkoxy, oxo, oximido,carbamido or hydroxy carbamido.
 13. The method of claim 11, wherein R⁸is selected from the group consisting of isopropyl and cyclopropyl. 14.The method of claim 11, wherein R¹, R³ and R⁸ are further substituted bysubstituents selected from the group consisting of halogen, hydroxy, C₁-C₄ alkoxy, C₃ -C₇ cycloalkoxy, or oxo.
 15. The method of claim 11,wherein R⁸ is selected from the group consisting of isopropyl, n-propyl,straight or branched butyl and straight or branched pentyl.
 16. Thecompound of claim 11, wherein R¹ and R³ are benzyl, optionallysubstituted with halogen, hydroxy, C₁ -C₄ alkoxy, or C₃ -C₇ cycloalkoxy.17. The method of claim 11, wherein said compound is selected from thegroup consistingof:3-(4-chlorobenzyl)-1-ethyl-8-isopropyl-6-thioxanthine;1,3-Di-(4-chlorobenzyl)-8-isopropyl-6-thioxanthine; and3-(3-Cyclopentyloxy-4-methoxy-benzyl)-1-ethyl-8-isopropyl-6-thioxanthine.18. A method of treating a patient suffering from a disease or disorderselected from the group consisting of asthma, allergies, depression, andrhinitis, comprising administering to the patient an effective amount ofa compound of the formula: ##STR8## wherein R¹ is selected from C₂ -C₆straight or branched alkyl, C₃ -C₆ cycloalkyl, and aralkyl wherein thealkyl moiety of said aralkyl is straight or branched or is cycloalkyl,wherein said alkyl, cycloalkyl, and aralkyl are optionally substitutedwith halogen, hydroxy, C₁ -C₄ alkoxy, C₃ -C₇ cycloalkoxy, oxo, oximido,carbamido or hydroxy carbamido;R² is selected from O and S; R³ isaralkyl wherein the alkyl moiety of said aralkyl is straight or branchedor is cycloalkyl, wherein said aralkyl is optionally substituted withhalogen, hydroxy, C₁ -C₄ alkoxy, C₃ -C₇ cycloalkoxy, oxo, oximido,carbamido or hydroxy carbamido; R⁶ is selected from O and S; and R⁸ isselected from isopropyl, n-propyl, cyclopropyl, butyl and pentyl, saidbutyl and pentyl being straight, branched or cyclic, or aralkylconsisting of an aryl moiety and a straight or branched C₁ -C₈ alkylenemoiety, wherein said isopropyl, n-propyl, cyclopropyl, butyl and pentyl,straight, branched or cyclic, or aralkyl are optionally substituted withhalogen, hydroxy, C₁ -C₄ alkoxy, C₃ -C₇ cycloalkoxy, oxo, oximido,carbamido or hydroxy carbamido; provided that R² and R⁶ are not both O.19. The method of claim 18, wherein R¹ and R³ of said compound areselected from the group consisting of alkyl and aralkyl.
 20. The methodof claim 18, wherein said compound is administered orally, topically, bysuppository, by inhalation, by insulation, or parenterally.
 21. Themethod of claim 18, wherein said compound is selected from the groupconsisting of:3-(4-chlorobenzyl)-1-ethyl-8-isopropyl-6-thioxanthine;1,3-Di-(4-chlorobenzyl)-8-isopropyl-6-thioxanthine; and3-(3-Cyclopentyloxy-4-methoxy-benzyl)-1-ethyl-8-isopropyl-6-thioxanthine.22. The method of claim 11 wherein R¹ is aralkyl wherein the alkylmoiety of said aralkyl is straight or branched or is cycloalkyl, andwherein said aralkyl is optionally substituted with halogen, hydroxy, C₁-C₄ alkoxy, C₃ -C₇ cycloalkoxy, oxo, oximido, carbamido or hydroxy. 23.The method of claim 18 wherein R¹ is aralkyl wherein the alkyl moiety ofsaid aralkyl is straight or branched or is cycloalkyl, and wherein saidaralkyl is optionally substituted with halogen, hydroxy, C₁ -C₄ alkoxy,C₃ -C₇ cycloalkoxy, oxo, oximido, carbamido or hydroxy.